Therapeutic substituted gamma lactams

ABSTRACT

Disclosed herein is a compound comprising 
                         
or a pharmaceutically acceptable salt or a prodrug thereof;
         wherein Y, A, X, R and D are as described.       
     Methods, compositions, and medicaments related thereto are also disclosed.

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application Ser.No. 61/037,626, filed Mar. 18, 2008, the disclosure of which is herebyincorporated in its entirety herein by reference.

BACKGROUND OF THE INVENTION

Ocular hypotensive agents are useful in the treatment of a number ofvarious ocular hypertensive conditions, such as post-surgical andpost-laser trabeculectomy ocular hypertensive episodes, glaucoma, and aspresurgical adjuncts.

Glaucoma is a disease of the eye characterized by increased intraocularpressure. On the basis of its etiology, glaucoma has been classified asprimary or secondary. For example, primary glaucoma in adults(congenital glaucoma) may be either open-angle or acute or chronicangle-closure. Secondary glaucoma results from pre-existing oculardiseases such as uveitis, intraocular tumor or an enlarged cataract.

The underlying causes of primary glaucoma are not yet known. Theincreased intraocular tension is due to the obstruction of aqueous humoroutflow. In chronic open-angle glaucoma, the anterior chamber and itsanatomic structures appear normal, but drainage of the aqueous humor isimpeded. In acute or chronic angle-closure glaucoma, the anteriorchamber is shallow, the filtration angle is narrowed, and the iris mayobstruct the trabecular meshwork at the entrance of the canal ofSchlemm. Dilation of the pupil may push the root of the iris forwardagainst the angle, and may produce pupilary block and thus precipitatean acute attack. Eyes with narrow anterior chamber angles arepredisposed to acute angle-closure glaucoma attacks of various degreesof severity.

Secondary glaucoma is caused by any interference with the flow ofaqueous humor from the posterior chamber into the anterior chamber andsubsequently, into the canal of Schlemm. Inflammatory disease of theanterior segment may prevent aqueous escape by causing completeposterior synechia in iris bombe, and may plug the drainage channel withexudates. Other common causes are intraocular tumors, enlargedcataracts, central retinal vein occlusion, trauma to the eye, operativeprocedures and intraocular hemorrhage.

Considering all types together, glaucoma occurs in about 2% of allpersons over the age of 40 and may be asymptotic for years beforeprogressing to rapid loss of vision. In cases where surgery is notindicated, topical β-adrenoreceptor antagonists have traditionally beenthe drugs of choice for treating glaucoma.

Certain eicosanoids and their derivatives are currently commerciallyavailable for use in glaucoma management. Eicosanoids and derivativesinclude numerous biologically important compounds such as prostaglandinsand their derivatives. Prostaglandins can be described as derivatives ofprostanoic acid which have the following structural formula:

Various types of prostaglandins are known, depending on the structureand substituents carried on the alicyclic ring of the prostanoic acidskeleton. Further classification is based on the number of unsaturatedbonds in the side chain indicated by numerical subscripts after thegeneric type of prostaglandin [e.g. prostaglandin E₁ (PGE₁),prostaglandin E₂ (PGE₂)], and on the configuration of the substituentson the alicyclic ring indicated by α or β [e.g. prostaglandin F_(2α)(PGF_(2β))].

In addition to the treatment of glaucoma, prostaglandin EP₂ selectiveagonists are believed to have several medical uses. For example, U.S.Pat. No. 6,437,146 teaches the use of prostaglandin EP₂ selectiveagonists “for treating or preventing inflammation and pain in joint andmuscle (e.g., rheumatoid arthritis, rheumatoid spondylitis,osteoarthritis, gouty arthritis, juvenile arthritis, etc.), inflammatoryskin condition (e.g., sunburn, burns, eczema, dermatitis, etc.),inflammatory eye condition (e.g., conjunctivitis, etc.), lung disorderin which inflammation is involved (e.g., asthma, bronchitis, pigeonfancier's disease, farmer's lung, etc.), condition of thegastrointestinal tract associated with inflammation (e.g., aphthousulcer, Chrohn's disease, atrophic gastritis, gastritis varialoforme,ulcerative colitis, coeliac disease, regional ileitis, irritable bowelsyndrome, etc.), gingivitis, inflammation, pain and tumescence afteroperation or injury, pyrexia, pain and other conditions associated withinflammation, allergic disease, systemic lupus crythematosus,scleroderma, polymyositis, tendinitis, bursitis, periarteritis nodose,rheumatic fever, Sjgren's syndrome, Behcet disease, thyroiditis, type Idiabetes, diabetic complication (diabetic microangiopathy, diabeticretinopathy, diabetic neohropathy, etc.), nephrotic syndrome, aplasticanemia, myasthenia gravis, uveitis contact dermatitis, psoriasis,Kawasaki disease, sarcoidosis, Hodgkin's disease, Alzheimers disease,kidney dysfunction (nephritis, nephritic syndrome, etc.), liverdysfunction (hepatitis, cirrhosis, etc.), gastrointestinal dysfunction(diarrhea, inflammatory bowel disease, etc.) shock, bone diseasecharacterized by abnormal bone metabolism such as osteoporosis(especially, postmenopausal osteoporosis), hypercalcemia,hyperparathyroidism, Paget's bone diseases, osteolysis, hypercalcemia ofmalignancy with or without bone metastases, rheumatoid arthritis,periodonritis, osteoarthritis, ostealgia, osteopenia, cancer cachexia,calculosis, lithiasis (especially, urolithiasis), solid carcinoma,mesangial proliferative glomerulonephritis, edema (e.g. cardiac edema,cerebral edema, etc.), hypertension such as malignant hypertension orthe like, premenstrual tension, urinary calculus, oliguria such as theone caused by acute or chronic failure, hyperphosphaturia, or the like.”

U.S. Pat. No. 6,710,072 teaches the use of EP2 agonists for thetreatment or prevention of “osteoporosis, constipation, renal disorders,sexual dysfunction, baldness, diabetes, cancer and in disorder of immuneregulation . . . various pathophysiological diseases including acutemyocardial infarction, vascular thrombosis, hypertension, pulmonaryhypertension, ischemic heart disease, congestive heart failure, andangina pectoris.”

SUMMARY OF THE INVENTION

Disclosed herein are compounds useful in treating glaucoma, inflammatorybowel disease, baldness, the stimulation of hair growth, and thestimulation of the conversion of vellus hair to terminal hair. Thecompounds themselves are disclosed below.

DESCRIPTION OF THE INVENTION

Disclosed herein is a compound comprising

or a pharmaceutically acceptable salt or a prodrug thereof;wherein

-   Y is

-   A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1    or 2 carbon atoms may be substituted with S or O; or A is    —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene or    heterointerarylene, the sum of m and o is from 1 to 4, and wherein    one CH₂ may be substituted with S or O;-   X is S or O;-   R is H; or alkyl, acyl, alkylsulfonyl, or alkylsulfamoyl having from    1 to 6 carbon atoms; and-   D is aryl or heteroaryl.

Unless stereochemistry is explicitly depicted, a structure is intendedto include every possible stereoisomer, both pure or in any possiblemixture. Compounds of the stereochemistry shown below, orpharmaceutically acceptable salts or prodrugs thereof, are particularlyuseful.

In relation to the identity of A disclosed in the chemical structurespresented herein, A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or—CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms may be substituted with Sor O; or A is —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene orheterointerarylene, the sum of m and o is from 1 to 4, and wherein oneCH₂ may be substituted with S or O.

While not intending to be limiting, A may be —(CH₂)₆—, cis—CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—.

Alternatively, A may be a group which is related to one of these threemoieties in that any carbon is substituted with S and/or O. For example,while not intending to limit the scope of the invention in any way, Amay be an S substituted moiety such as one of the following or the like.

Alternatively, while not intending to limit the scope of the inventionin any way, A may be an O substituted moiety such as one of thefollowing or the like.

Alternatively, while not intending to limit the scope of the inventionin any way, A may have both an O and an S substituted into the chain,such as one of the following or the like.

Alternatively, while not intending to limit the scope of the inventionin any way, in certain embodiments A is —(CH₂)_(m)—Ar—(CH₂)_(o)— whereinAr is interarylene or heterointerarylene, the sum of m and o is from 1to 4, and wherein one CH₂ may be substituted with S or O. In otherwords, while not intending to limit the scope of the invention in anyway,

-   in one embodiment A comprises from 1 to 4 CH₂ moieties and Ar, e.g.    —CH₂—Ar—, —(CH₂)₂—Ar—, —CH₂—Ar—CH₂—, —CH₂Ar—(CH₂)₂—,    —(CH₂)₂—Ar—(CH₂)₂—, and the like;-   in another embodiment A comprises O, from 0 to 3 CH₂ moieties, and    Ar, e.g., —O—Ar—, Ar—CH₂—O—, —O—Ar—(CH₂)₂—, —O—CH₂—Ar—,    —O—CH₂—Ar—(CH₂)₂, and the like; or-   in another embodiment A comprises S, from 0 to 3 CH₂ moieties, and    Ar, e.g., —S—Ar—, Ar—CH₂—S—, —S—Ar—(CH₂)₂—, —S—CH₂—Ar—,    —S—CH₂—Ar—(CH₂)₂, —(CH₂)₂—S—Ar, and the like.

In another embodiment, the sum of m and o is from 2 to 4 wherein one CH₂may be substituted with S or O.

In another embodiment, the sum of m and o is 3 wherein one CH₂ may besubstituted with S or O.

In another embodiment, the sum of m and o is 2 wherein one CH₂ may besubstituted with S or O.

In another embodiment, the sum of m and o is 4 wherein one CH₂ may besubstituted with S or O.

Interarylene or heterointerarylene refers to an aryl ring or ring systemor a heteroaryl ring or ring system which connects two other parts of amolecule, i.e. the two parts are bonded to the ring in two distinct ringpositions. Interarylene or heterointerarylene may be substituted orunsubstituted. Unsubstituted interarylene or heterointerarylene has nosubstituents other than the two parts of the molecule it connects.Substituted interarylene or heterointerarylene has substituents inaddition to the two parts of the molecule it connects.

In one embodiment, Ar is substituted or unsubstituted interphenylene,interthienylene, interfurylene, interpyridinylene, interoxazolylene, andinterthiazolylene. In another embodiment Ar is interphenylene (Ph). Inanother embodiment A is —(CH₂)₂-Ph-. While not intending to limit scopeof the invention in any way, substituents may have 4 or less heavyatoms, or in other words, non hydrogen atoms. Any number of hydrogenatoms required for a particular substituent will also be included. Thus,the substituent may be

-   hydrocarbyl having up to 4 carbon atoms, including alkyl up to C₄,    alkenyl, alkynyl, and the like;-   hydrocarbyloxy up to C₃;-   CF₃;-   halo, such as F, Cl, or Br;-   hydroxyl;-   NH₂ and alkylamine functional groups up to C₃;-   other N or S containing substituents;-   and the like.

In one embodiment A is —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar isinterphenylene, the sum of m and o is from 1 to 3, and wherein one CH₂may be substituted with S or O.

In another embodiment A is —CH₂—Ar—OCH₂—. In another embodiment A is—CH₂—Ar—OCH₂— and Ar is interphenylene. In another embodiment, Ar isattached at the 1 and 3 positions, otherwise known as m-interphenylene,such as when A has the structure shown below.

In another embodiment A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or—CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms may be substituted with Sor O; or A is —(CH₂)₂-Ph- wherein one CH₂ may be substituted with S orO.

In another embodiment A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or—CH₂C≡C—(CH₂)₃—, wherein 1 or 2 carbon atoms may be substituted with Sor O; or A is —(CH₂)₂-Ph-.

In other embodiments, A has one of the following structures, where Y isattached to the aromatic or heteroaromatic ring.

In another embodiment, A is selected from the group

In another embodiment A is —CH₂OCH₂Ar.

In another embodiment A is —CH₂SCH₂Ar.

In another embodiment A is —(CH₂)₃Ar.

In another embodiment A is —CH₂O(CH₂)₄.

In another embodiment A is —CH₂S(CH₂)₄.

In another embodiment A is —(CH₂)₆—.

In another embodiment A is cis —CH₂CH=CH—(CH₂)₃—.

In another embodiment A is —CH₂C≡C—(CH₂)₃—.

In another embodiment A is —S(CH₂)₃S(CH₂)₂—.

In another embodiment A is —(CH₂)₄OCH₂—.

In another embodiment A is cis —CH₂CH=CH—CH₂OCH₂—.

In another embodiment A is —CH₂CH≡CH—CH₂OCH₂—.

In another embodiment A is —(CH₂)₂S(CH₂)₃—.

In another embodiment A is —CH₂-Ph-OCH₂—, wherein Ph is interphenylene.

In another embodiment A is —CH₂-mPh-OCH₂—, wherein mPh ism-interphenylene.

In another embodiment A is —CH₂—O—(CH₂)₄—.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interthienylene.

In another embodiment A is —CH₂—O—CH₂—Ar—, wherein Ar is2,5-interfurylene.

X is S or O. Thus, compounds according to one of the formulas shownbelow, or pharmaceutically acceptable salts or prodrugs thereof, arepossible.

R is H; or alkyl, acyl, alkylsulfonyl, or alkylsulfamoyl having from 1to 6 carbon atoms.

Alkyl is hydrocarbyl (i.e. all C and H atoms) having no double or triplebonds including:

-   linear alkyl such as methyl, ethyl, propyl, n-butyl, n-pentyl,    n-hexyl, and the like;-   branched alkyl such as isopropyl, branched butyl isomers (i.e.    sec-butyl, tert-butyl, etc), branched pentyl isomers (i.e.    isopentyl, etc), branched hexyl isomers, and higher branched alkyl    fragments;-   cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,    cycloheptyl, etc.; and alkyl fragments consisting of both cyclic and    noncyclic components, whether linear or branched, which may be    attached to the remainder of the molecule at any available position    including terminal, internal, or ring carbon atoms.

Acyl has the meaning normally understood in the art. In other words,acyl is alkyl attached to a carbonyl carbon, i.e. alkyl-C(═O)—.

Alkylsulfonyl has the meaning normally understood in the art. In otherwords, alkylsulfonyl is alkyl attached to a sulfonyl sulfur, i.e.alkyl-SO₂—.

Alkylsulfamoyl has the meaning normally understood in the art. In otherwords, alkylsulfamoyl is alkyl attached to a sulfamoyl nitrogen, i.e.alkyl-N—SO₂—.

Thus, compounds according to one of the structures shown below, orpharmaceutically acceptable salts or prodrugs thereof, are possible,where R³ is independently H or C₁₋₆ alkyl.

Particular embodiments contemplated include compounds according to thestructures below, or pharmaceutically acceptable salts or prodrugsthereof.

D is aryl or heteroaryl.

Aryl is an unsubstituted or substituted aromatic ring or ring systemsuch as phenyl, naphthyl, biphenyl, and the like.

Heteroaryl is aryl having one or more N, O, or S atoms in the ring, i.e.a ring carbon is substituted by N, O, or S. While not intending to belimiting, examples of heteroaryl include unsubstituted or substitutedthienyl, pyridinyl, furyl, benzothienyl, benzofuryl, imidizololyl,indolyl, and the like.

The substituents of aryl or heteroaryl may have up to 12 non-hydrogenatoms each and as many hydrogen atoms as necessary. Thus, while notintending to limit the scope of the invention in any way, thesubstituents may be:

-   hydrocarbyl, such as alkyl, alkenyl, alkynyl, and the like,    including linear, branched or cyclic hydrocarbyl, and combinations    thereof;-   hydrocarbyloxy, meaning O-hydrocarbyl such as OCH₃, OCH₂CH₃,    O-cyclohexyl, etc, up to 11 carbon atoms;-   hydroxyhydrocarbyl, meaning hydrocarbyl-OH such as CH₂OH, C(CH₃)₂OH,    etc, up to 11 carbon atoms;-   nitrogen substituents such as NO₂, CN, and the like, including-   amino, such as NH₂, NH(CH₂CH₃OH), NHCH₃, and the like up to 11    carbon atoms;-   carbonyl substituents, such as CO₂H, ester, amide, and the like;-   halogen, such as chloro, fluoro, bromo, and the like-   fluorocarbyl, such as CF₃, CF₂CF₃, etc.;-   phosphorous substituents, such as PO₃ ²⁻, and the like;-   sulfur substituents, including S-hydrocarbyl, SH, SO₃H,    SO₂-hydrocarbyl, SO₃-hydrocarbyl, and the like.

In certain embodiments, the number of non-hydrogen atoms is 6 or less ina substituent. In other embodiments, the number of non-hydrogen atoms is3 or less in a substituent. In other embodiments, the number ofnon-hydrogen atoms on a substituent is 1.

In certain embodiments, the substituents contain only hydrogen, carbon,oxygen, halogen, nitrogen, and sulfur. In other embodiments, thesubstituents contain only hydrogen, carbon, oxygen, and halogen.

Unless otherwise indicated, references to aryl, heteroaryl, phenyl,thienyl, benzothienyl, and the like are intended to mean both thesubstituted and the unsubstituted moiety.

Thus, compounds wherein D is any of the above classes or species of arylor heteroaryl are contemplated herein.

Further, while not intending to limit the scope of the invention in anyway, in one embodiment D is phenyl. In another embodiment D ischlorophenyl, meaning phenyl with one or more chloro substituents. Inanother embodiment D is 3,5-dichlorophenyl. In another embodiment D isunsubstituted phenyl.

Compounds according to the structures below, or pharmaceuticallyacceptable salts or prodrugs thereof, are contemplated, wherein R⁴ isindependently a substituent having from 0 to 10 carbon atoms and from 0to 5 heteroatoms selected from the group consisting of Cl, F, Br, O, N,and S; and q is 0, 1, 2, 3, or 4. R⁴ may also form a ring with twocarbon atoms of the phenyl ring.

In one embodiment R⁴ is C₁₋₆ alkyl, C₁₋₆ hydroxyalkyl, C₁₋₆ O-alkyl,C₁₋₆ aryl, C₁₋₆ alkylsulfamoyl, C₁₋₁₀ aryl, C₁₋₁₀ arylalkyl, C₁₋₁₀hydroxyarylalkyl, Cl, F, Br, CF₃, COCF₃, SO₂NH₂, NO₂, OH, or CN.

Arylalkyl is alkyl with an aryl substituent.

Hydroxyarylalkyl is alkyl with an aryl and a hydroxyl substituent.

Each of the compounds or structures shown below represents an individualembodiment contemplated herein. Pharmaceutically acceptable salts orprodrugs of these compounds or structures are also contemplated.

Specifically Contemplated Embodiments

Embodiments are contemplated for each of the compounds or structuraldescriptions of compounds disclosed herein. Furthermore, for eachcompound or structure a method of treating glaucoma or ocularhypertension, a method of treating inflammatory bowel disease, a methodof manufacturing a medicament for the treatment of glaucoma or ocularhypertension, a method of manufacturing a medicament for the treatmentof inflammatory bowel disease, and a composition comprising atherapeutically effective amount of the compound is specificallycontemplated. Furthermore, the embodiments disclosed below arespecifically contemplated.

Methods of Manufacturing A Medicament

Glaucoma or Ocular Hypertension

One embodiment is use of a compound in the manufacture of a medicamentfor the treatment of glaucoma or ocular hypertension, said compoundcomprising

or a pharmaceutically acceptable salt or a prodrug thereof;wherein

-   Y is

-   A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1    or 2 carbon atoms may be substituted with S or O; or A is    —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene or    heterointerarylene, the sum of m and o is from 1 to 4, and wherein    one CH₂ may be substituted with S or O;-   X is S or O;-   R is H; or alkyl, acyl, alkylsulfonyl, or alkylsulfamoyl having from    1 to 6 carbon atoms; and-   D is aryl or heteroaryl.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof

-   wherein R⁴ is independently a substituent having from 0 to 10 carbon    atoms and from 0 to 5 heteroatoms selected from the group consisting    of Cl, F, Br, O, N, and S;-   q is 0, 1, 2, 3, or 4; and-   wherein two R⁴ moieties may form a ring with two carbon atoms of the    phenyl ring.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.Inflammatory Bowel Disease

One embodiment is use of a compound in the manufacture of a medicamentfor the treatment of inflammatory bowel disease. said compoundcomprising

or a pharmaceutically acceptable salt or a prodrug thereof;wherein

-   Y is

-   A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1    or 2 carbon atoms may be substituted with S or O; or A is    —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene or    heterointerarylene, the sum of m and o is from 1 to 4, and wherein    one CH₂ may be substituted with S or O;-   X is S or O;-   R is H; or alkyl, acyl, alkylsulfonyl, or alkylsulfamoyl having from    1 to 6 carbon atoms; and-   D is aryl or heteroaryl.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof

-   wherein R⁴ is independently a substituent having from 0 to 10 carbon    atoms and from 0 to 5 heteroatoms selected from the group consisting    of Cl, F, Br, O, N, and S;-   q is 0, 1, 2, 3, or 4; and-   wherein two R⁴ moieties may form a ring with two carbon atoms of the    phenyl ring.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment the inflammatory bowel disease is ulcerativecolitis.

In another embodiment the inflammatory bowel disease is Crohn's disease.

Baldness

One embodiment is use of a compound in the manufacture of a medicamentfor the treatment of baldness.

-   said compound comprising

or a pharmaceutically acceptable salt or a prodrug thereof;wherein

-   Y is

-   A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1    or 2 carbon atoms may be substituted with S or O; or A is    —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene or    heterointerarylene, the sum of m and o is from 1 to 4, and wherein    one CH₂ may be substituted with S or O;-   X is S or O;-   R is H; or alkyl, acyl, alkylsulfonyl, or alkylsulfamoyl having from    1 to 6 carbon atoms; and-   D is aryl or heteroaryl.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof

-   wherein R⁴ is independently a substituent having from 0 to 10 carbon    atoms and from 0 to 5 heteroatoms selected from the group consisting    of Cl, F, Br, O, N, and S;-   q is 0, 1, 2, 3, or 4; and-   wherein two R⁴ moieties may form a ring with two carbon atoms of the    phenyl ring.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.Methods of TreatingGlaucoma or Ocular Hypertension

One embodiment is a method comprising administering a compound to amammal for the treatment of glaucoma or ocular hypertension,

-   said compound comprising

or a pharmaceutically acceptable salt or a prodrug thereof;wherein

-   Y is

-   A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1    or 2 carbon atoms may be substituted with S or O; or A is    —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene or    heterointerarylene, the sum of m and o is from 1 to 4, and wherein    one CH₂ may be substituted with S or O;-   X is S or O;-   R is H; or alkyl, acyl, alkylsulfonyl, or alkylsulfamoyl having from    1 to 6 carbon atoms; and-   D is aryl or heteroaryl.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof

-   wherein R⁴ is independently a substituent having from 0 to 10 carbon    atoms and from 0 to 5 heteroatoms selected from the group consisting    of Cl, F, Br, O, N, and S;-   q is 0, 1, 2, 3, or 4; and-   wherein two R⁴ moieties may form a ring with two carbon atoms of the    phenyl ring.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.Inflammatory Bowel Disease

One embodiment is a method comprising administering a compound to amammal for the treatment of inflammatory bowel disease.

-   said compound comprising

or a pharmaceutically acceptable salt or a prodrug thereof;wherein

-   Y is

-   A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1    or 2 carbon atoms may be substituted with S or O; or A is    —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene or    heterointerarylene, the sum of m and o is from 1 to 4, and wherein    one CH₂ may be substituted with S or O;-   X is S or O;-   R is H; or alkyl, acyl, alkylsulfonyl, or alkylsulfamoyl having from    1 to 6 carbon atoms; and-   D is aryl or heteroaryl.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof

-   wherein R⁴ is independently a substituent having from 0 to 10 carbon    atoms and from 0 to 5 heteroatoms selected from the group consisting    of Cl, F, Br, O, N, and S;-   q is 0, 1, 2, 3, or 4; and-   wherein two R⁴ moieties may form a ring with two carbon atoms of the    phenyl ring.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment the inflammatory bowel disease is ulcerativecolitis.

In another embodiment the inflammatory bowel disease is Crohn's disease.

Compounds

One embodiment is a compound comprising

or a pharmaceutically acceptable salt or a prodrug thereof;wherein

-   Y is

-   A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1    or 2 carbon atoms may be substituted with S or O; or A is    —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene or    heterointerarylene, the sum of m and o is from 1 to 4, and wherein    one CH₂ may be substituted with S or O;-   X is S or O;-   R is H; or alkyl, acyl, alkylsulfonyl, or alkylsulfamoyl having from    1 to 6 carbon atoms; and-   D is aryl or heteroaryl.

Another embodiment is a compound comprising

or a pharmaceutically acceptable salt or a prodrug thereof.

Another embodiment is a compound comprising

or a pharmaceutically acceptable salt or a prodrug thereof.

Another embodiment is a compound comprising

or a pharmaceutically acceptable salt or a prodrug thereof.

Another embodiment is a compound comprising

or a pharmaceutically acceptable salt or a prodrug thereof

-   wherein R⁴ is independently a substituent having from 0 to 10 carbon    atoms and from 0 to 5 heteroatoms selected from the group consisting    of Cl, F, Br, O, N, and S;-   q is 0, 1, 2, 3, or 4; and-   wherein two R⁴ moieties may form a ring with two carbon atoms of the    phenyl ring.

Another embodiment is a compound comprising

or a pharmaceutically acceptable salt or a prodrug thereof.

Another embodiment is a compound comprising

or a pharmaceutically acceptable salt or a prodrug thereof.

Another embodiment is a compound comprising

or a pharmaceutically acceptable salt or a prodrug thereof.Composition

Another embodiment is a composition wherein said composition comprises acompound

or a pharmaceutically acceptable salt or a prodrug thereof;wherein

-   Y is

-   A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1    or 2 carbon atoms may be substituted with S or O; or A is    —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene or    heterointerarylene, the sum of m and o is from 1 to 4, and wherein    one CH₂ may be substituted with S or O;-   X is S or O;-   R is H; or alkyl, acyl, alkylsulfonyl, or alkylsulfamoyl having from    1 to 6 carbon atoms; and-   D is aryl or heteroaryl.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof

-   wherein R⁴ is independently a substituent having from 0 to 10 carbon    atoms and from 0 to 5 heteroatoms selected from the group consisting    of Cl, F, Br, O, N, and S;-   q is 0, 1, 2, 3, or 4; and-   wherein two R⁴ moieties may form a ring with two carbon atoms of the    phenyl ring.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment the inflammatory bowel disease is ulcerativecolitis.

In another embodiment the inflammatory bowel disease is Crohn's disease.

Methods of Treating

One embodiment is a composition comprising a compound, wherein saidcomposition is ophthalmically acceptable,

-   said compound comprising

or a pharmaceutically acceptable salt or a prodrug thereof;wherein

-   Y is

-   A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1    or 2 carbon atoms may be substituted with S or O; or A is    —(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene or    heterointerarylene, the sum of m and o is from 1 to 4, and wherein    one CH₂ may be substituted with S or O;-   X is S or O;-   R is H; or alkyl, acyl, alkylsulfonyl, or alkylsulfamoyl having from    1 to 6 carbon atoms; and-   D is aryl or heteroaryl.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof

-   wherein R⁴ is independently a substituent having from 0 to 10 carbon    atoms and from 0 to 5 heteroatoms selected from the group consisting    of Cl, F, Br, O, N, and S;-   q is 0, 1, 2, 3, or 4; and-   wherein two R⁴ moieties may form a ring with two carbon atoms of the    phenyl ring.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.

In another embodiment said compound comprises

or a pharmaceutically acceptable salt or a prodrug thereof.

The compounds of disclosed herein are useful for the prevention ortreatment of glaucoma or ocular hypertension in mammals, or for themanufacture of a medicament for the treatment of glaucoma or ocularhypertension. They are also useful for the treatment of those diseasesdisclosed in the art as being amenable to treatment by prostaglandin EP₂agonist, such as the ones listed previously.

A “pharmaceutically acceptable salt” is any salt that retains theactivity of the parent compound and does not impart any additionaldeleterious or untoward effects on the subject to which it isadministered and in the context in which it is administered compared tothe parent compound. A pharmaceutically acceptable salt also refers toany salt which may form in vivo as a result of administration of anacid, another salt, or a prodrug which is converted into an acid orsalt.

Pharmaceutically acceptable salts of acidic functional groups may bederived from organic or inorganic bases. The salt may comprise a mono orpolyvalent ion. Of particular interest are the inorganic ions lithium,sodium, potassium, calcium, and magnesium. Organic salts may be madewith amines, particularly ammonium salts such as mono-, di- and trialkylamines or ethanol amines. Salts may also be formed with caffeine,tromethamine and similar molecules. Hydrochloric acid or some otherpharmaceutically acceptable acid may form a salt with a compound thatincludes a basic group, such as an amine or a pyridine ring.

A “prodrug” is a compound which is converted to a therapeutically activecompound after administration, and the term should be interpreted asbroadly herein as is generally understood in the art. While notintending to limit the scope of the invention, conversion may occur byhydrolysis of an ester group or some other biologically labile group.Generally, but not necessarily, a prodrug is inactive or less activethan the therapeutically active compound to which it is converted. Esterprodrugs of the compounds disclosed herein are specificallycontemplated. An ester may be derived from a carboxylic acid of C1 (i.e.the terminal carboxylic acid of a natural prostaglandin), or an estermay be derived from a carboxylic acid functional group on another partof the molecule, such as on a phenyl ring. While not intending to belimiting, an ester may be an alkyl ester, an aryl ester, or a heteroarylester. The term alkyl has the meaning generally understood by thoseskilled in the art and refers to linear, branched, or cyclic alkylmoieties. C₁₋₆ alkyl esters are particularly useful, where alkyl part ofthe ester has from 1 to 6 carbon atoms and includes, but is not limitedto, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl,t-butyl, pentyl isomers, hexyl isomers, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, and combinations thereof having from 1-6 carbonatoms, etc.

Those skilled in the art will readily understand that for administrationor the manufacture of medicaments the compounds disclosed herein can beadmixed with pharmaceutically acceptable excipients which per se arewell known in the art. Specifically, a drug to be administeredsystemically, it may be confected as a powder, pill, tablet or the like,or as a solution, emulsion, suspension, aerosol, syrup or elixirsuitable for oral or parenteral administration or inhalation.

For solid dosage forms or medicaments, non-toxic solid carriers include,but are not limited to, pharmaceutical grades of mannitol, lactose,starch, magnesium stearate, sodium saccharin, the polyalkylene glycols,talcum, cellulose, glucose, sucrose and magnesium carbonate. The soliddosage forms may be uncoated or they may be coated by known techniquesto delay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. They may also be coated by the technique described inthe U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release. Liquid pharmaceuticallyadministrable dosage forms can, for example, comprise a solution orsuspension of one or more of the presently useful compounds and optionalpharmaceutical adjutants in a carrier, such as for example, water,saline, aqueous dextrose, glycerol, ethanol and the like, to therebyform a solution or suspension. If desired, the pharmaceuticalcomposition to be administered may also contain minor amounts ofnontoxic auxiliary substances such as wetting or emulsifying agents, pHbuffering agents and the like. Typical examples of such auxiliary agentsare sodium acetate, sorbitan monolaurate, triethanolamine, sodiumacetate, triethanolamine oleate, etc. Actual methods of preparing suchdosage forms are known, or will be apparent, to those skilled in thisart; for example, see Remington's Pharmaceutical Sciences, MackPublishing Company, Easton, Pa., 16th Edition, 1980. The composition ofthe formulation to be administered, in any event, contains a quantity ofone or more of the presently useful compounds in an amount effective toprovide the desired therapeutic effect.

Parenteral administration is generally characterized by injection,either subcutaneously, intramuscularly or intravenously. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions, solid forms suitable for solution or suspension in liquidprior to injection, or as emulsions. Suitable excipients are, forexample, water, saline, dextrose, glycerol, ethanol and the like. Inaddition, if desired, the injectable pharmaceutical compositions to beadministered may also contain minor amounts of non-toxic auxiliarysubstances such as wetting or emulsifying agents, pH buffering agentsand the like.

The amount of the presently useful compound or compounds administered isdependent on the therapeutic effect or effects desired, on the specificmammal being treated, on the severity and nature of the mammal'scondition, on the manner of administration, on the potency andpharmacodynamics of the particular compound or compounds employed, andon the judgment of the prescribing physician. The therapeuticallyeffective dosage of the presently useful compound or compounds may be inthe range of about 0.5 or about 1 to about 100 mg/kg/day.

A liquid which is ophthalmically acceptable is formulated such that itcan be administered topically to the eye. The comfort should bemaximized as much as possible, although sometimes formulationconsiderations (e.g. drug stability) may necessitate less than optimalcomfort. In the case that comfort cannot be maximized, the liquid shouldbe formulated such that the liquid is tolerable to the patient fortopical ophthalmic use. Additionally, an ophthalmically acceptableliquid should either be packaged for single use, or contain apreservative to prevent contamination over multiple uses.

For ophthalmic application, solutions or medicaments are often preparedusing a physiological saline solution as a major vehicle. Ophthalmicsolutions should preferably be maintained at a comfortable pH with anappropriate buffer system. The formulations may also containconventional, pharmaceutically acceptable preservatives, stabilizers andsurfactants.

Preservatives that may be used in the pharmaceutical compositions of thepresent invention include, but are not limited to, benzalkoniumchloride, chlorobutanol, thimerosal, phenylmercuric acetate andphenylmercuric nitrate. A useful surfactant is, for example, Tween 80.Likewise, various useful vehicles may be used in the ophthalmicpreparations of the present invention. These vehicles include, but arenot limited to, polyvinyl alcohol, povidone, hydroxypropyl methylcellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl celluloseand purified water.

Tonicity adjustors may be added as needed or convenient. They include,but are not limited to, salts, particularly sodium chloride, potassiumchloride, mannitol and glycerin, or any other suitable ophthalmicallyacceptable tonicity adjustor.

Various buffers and means for adjusting pH may be used so long as theresulting preparation is ophthalmically acceptable. Accordingly, buffersinclude acetate buffers, citrate buffers, phosphate buffers and boratebuffers. Acids or bases may be used to adjust the pH of theseformulations as needed.

In a similar vein, an ophthalmically acceptable antioxidant for use inthe present invention includes, but is not limited to, sodiummetabisulfite, sodium thiosulfate, acetylcysteine, butylatedhydroxyanisole and butylated hydroxytoluene.

Other excipient components which may be included in the ophthalmicpreparations are chelating agents. A useful chelating agent is edetatedisodium, although other chelating agents may also be used in place orin conjunction with it.

The ingredients are usually used in the following amounts:

Ingredient Amount (% w/v) active ingredient about 0.001-5 preservative  0-0.10 vehicle   0-40 tonicity adjustor   1-10 buffer 0.01-10 pHadjustor q.s. pH 4.5-7.5 antioxidant as needed surfactant as neededpurified water as needed to make 100%Applications for Stimulating Hair Growth

In one embodiment, the compounds disclosed herein can be useful in thetreatment of baldness and/or hair loss. Alopecia (baldness) is adeficiency of either normal or abnormal hair, and is primarily acosmetic problem in humans. It is a deficiency of terminal hair, thebroad diameter, colored hair that is readily seen. However, in the socalled bald person, although there is a noticeable absence of terminalhair, the skin does contain vellus hair, which is a fine colorless hairwhich may require microscopic examination to determine its presence.This vellus hair is a precursor to terminal hair.

The compounds described herein can be used to stimulate, such as theconversion of vellus hair to growth as terminal hair, as well asincreasing the rate of growth of terminal hair. The utility of thecompounds described herein for the simulation of hair growth wasdiscovered as follows.

In the course of treating patients having glaucoma, treatment may onlybe appropriate in one eye. Within the course of daily practice, it wasdiscovered that a patient who had been treated with bimatoprost, aprostaglandin analogue, developed lashed that were longer, thicker, andfuller in the treated eye than in the non-treated eye. On examination,the difference was found to be very striking. The lashes were longer andhad a fuller, denser appearance in the treated eye. The lash appearanceon the lids of the treated eyes would have appeared quite attractive ifit represented a bilateral phenomenon. As a result of its asymmetricnature, the long lashes on one side could be construed as disturbingfrom a cosmetic standpoint. A systemic examination was preformed as aresult of the asymmetric phenomenon. It soon became apparent that thisaltered appearance was not an isolated finding. Comparison of the lidsof patients who were taking bimatoprost in only one eye revealed subtlechanges in the lashed and adjacent hairs of the bimatoprost-treated sidein several patients. Definite differences could be identified to varyingdegrees in the lashes and adjacent hairs of all patients who were takingthe drug on a unilateral basis for longer than 6 months.

The changes in the lashes were apparent on gross inspection in severalpatients once attention was focused on the issue. In those with lightcolored hair and lashes, the differences were only seen easily with theaid of the high magnification and lighting capabilities of the slit lampbiomicroscope. In the course of glaucoma follow-up examination,attention is generally immediately focused on the eye itself. As aresult of the high power magnification needed only one eye is seen at atime and the eye is seen at a high enough power that the lashes are notin focus. At these higher powers, any lash asymmetry between the twoeyes is not likely to be noticed except by careful systematic comparisonof the lashes and adjacent hairs of the eyelids of the two eyes.

Observed parameters leading to the conclusion that more robust hairgrowth occurred in the treatment area following administration of theprostaglandin analogue were multiple. They included increased length oflashed, increased number of lashes along the normal lash line, increasedthickness and luster of lashes, increased auxiliary lash-like terminalhair in transitional areas adjacent to areas of normal lash growth,increased auxiliary lash-like terminal hairs at the medial and lateralcanthal area, increased pigmentation of the lashes, increased numbers,increased length, as well as increased luster, and thickness of finehair on the skin of the adjacent lid, and finally, increasedperpendicular angulation of lashes and lash-like terminal hairs. Theconclusion that hair growth is stimulated by prostaglandin analoguessuch as bimatoprost is thus supported not by evidence of a difference ina single parameter, but is based on multiple parameters of hairappearance in treated versus control areas in many subjects.

The compounds described herein are prostaglandin analogues and thereforehave similar activities as bimatoprost, contain structural similarities,and therefore are expected to stimulate hair growth and stimulation ofthe conversion of vellus hair to terminal hair. In one embodiment, thecompounds described herein and their prodrugs can be used for thestimulation of hair growth. As used herein, hair growth includes hairassociated with the scalp, eyebrows, eyelids, beard, and other areas ofthe skin of animals.

In one embodiment, the compound is mixed with a dermatologicallycompatible vehicle or carrier. The vehicle, which may be employed forpreparing compositions as described herein, may comprise, for example,aqueous solutions such as e.g., physiological salines, oil solutions, orointments. The vehicle furthermore may contain dermatologicallycompatible preservatives such as e.g., benzalkonium chloride,surfactants like e.g., polysorbate 80, liposomes or polymers, forexample, methyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone andhyaluronic acid; these may be used for increasing the viscosity.Furthermore, it is also possible to use soluble or insoluble druginserts when the drug is to be administered.

In one embodiment, dermatological compositions can be formulated fortopical treatment for the stimulation of hair growth which comprises aneffective hair growth simulating amount of one or more compounds asdefined above and a dermatologically compatible carrier. Effectiveamounts of the active compounds may be determined by one of ordinaryskill in the art, but will vary depending on the compound employed,frequency of application and desired result. The compound will generallyrange from about 0.0000001 to about 50% by weight of the dermatologicalcomposition. Preferably, the compound will range from about 0.001 toabout 50% by weight of total dermatological composition, more preferablyfrom about 0.1 to about 30% by weight of the composition.

In one embodiment, the application of the present compounds forstimulation of hair growth finds applications in mammalian species,including both humans and animals. In humans, the compounds describedherein can be applied for example, to the scalp, face beard, head, pubicarea, upper lip, eyebrows, and eyelids. In animal raised for theirpelts, e.g., mink, the compounds described herein can be applied overthe entire surface of the body to improve the overall pelt forcommercial reasons. The process can also be used for cosmetic reasons inanimals, e.g., applied to the skin of dogs and cats having bald patchesdue to mange or other diseases causing a degree of alopecia.

The pharmaceutical compositions contemplated for the stimulation of hairgrowth include pharmaceutical compositions suited for topical and localaction. The term “topical” as employed herein relates to the use of acompound, as described herein, incorporated in a suitable pharmaceuticalcarrier, and applied at the site of thinning hair or baldness forexertion of local action. Accordingly, such topical compositions includethose pharmaceutical forms in which the compound is applied externallyby direct contact with the skin to be treated. Conventionalpharmaceutical forms for this purpose include ointments, liniments,creams, shampoos, lotions, pastes, jellies, sprays, aerosols, and thelike, and may be applied in patches or impregnated dressings dependingon the part of the body to be treated. The term “ointment” embracesformulations (including creams) having oleaginous, water-soluble andemulsion-type bases, e.g., petrolatum, lanolin, polyethylene glycols, aswell as mixtures of these.

Typically, the compounds can be applied repeatedly for the sustainedperiod of time topically on the part of the body to be treated, forexample, the eyelids, eyebrows, skin or scalp. The preferred dosageregimen will generally involve regular, such as daily, administrationfor a period of treatment of at least one month, more preferably atleast three months, and most preferably, at least six months.

For topical use on the eyelids or eyebrows, the active compounds can beformulated in aqueous solutions, creams, ointments, or oils exhibitingphysologicla acceptable osmolarity by addition of pharmaceuticallyacceptable buffers and salts. such formulations may or may not,depending on the dispenser, contain preservatives such as benzalkoniumchloride, chlorhexidine, chlorobutanol, parahydroxybenzoic acids andphenylmercuric salts such as nitrate, chloride, acetate, and borate, orantioxidants, as well as additives like EDTA, sorbitol, boric acid andthe like as additives. Furthermore, particularly aqueous solutions maycontain viscosity increasing agents such as polysaccharides, e.g.,methylcellulose, mucopolysaccharides, e.g., hyaluronic acid andchondroitin sulfate, or poly alcohol, e.g., polyvinylalcohol. Variousslow releasing gels and matricies may also be employed as well assoluble and insoluble ocular inserts, for instance, based on substancesforming in situ gels. Depending on the actual formation and compound tobe used, various amounts of the drug and different dose regimens may beemployed. Typically, the daily amount of compound for treatment of theeyelid may be about 0.1 ng to about 100 mg per eyelid.

For topical use on the skin and scalp, the compound can beadvantageously formulated using ointments, creams, liniments or patchesas a carrier of the active ingredient. Also, these formulations may ormay not contain preservatives, depending on the dispenser and nature ofuse. Such preservatives include those mentioned above, and methyl-,propyl-, or butyl-parahydroxybenzoic acid, betain, chlorhexidine,benzalkonium chloride, and the like. Various matricies for the slowrelease delivery may also be used. Typically, the dose to be applied onthe scalp is in the range of about 0.1 ng to about 100 mg per day, morepreferably about 1 ng to about 10 mg per day, and most preferably about10 ng to about 1 mg per day depending on the compound and theformulation. To achieve the daily amount of medication depending on theformulation, the compound may be administered once or several timesdaily with or without antioxidants.

For topical use, creams, ointments, gels, solutions or suspensions,etc., containing the compound disclosed herein are employed. Topicalformulations may generally be comprised of a pharmaceutical carrier,cosolvent, emulsifier, penetration enhancer, preservative system, andemollient.

The actual dose of the active compounds of the present invention dependson the specific compound, and on the condition to be treated; theselection of the appropriate dose is well within the knowledge of theskilled artisan.

The compounds disclosed herein are also useful in combination with otherdrugs useful for the treatment of glaucoma or other conditions.

For the treatment of glaucoma, combination treatment with the followingclasses of drugs are contemplated:

-   β-Blockers (or β-adrenergic antagonists) including carteolol,    levobunolol, metiparanolol, timolol hemihydrate, timolol maleate,    β1-selective antagonists such as betaxolol, and the like, or    pharmaceutically acceptable salts or prodrugs thereof;-   Adrenergic Agonists including-   non-selective adrenergic agonists such as epinephrine borate,    epinephrine hydrochloride, and dipivefrin, and the like, or    pharmaceutically acceptable salts or prodrugs thereof; and-   α₂-selective adrenergic agonists such as apraclonidine, brimonidine,    and the like, or pharmaceutically acceptable salts or prodrugs    thereof;-   Carbonic Anhydrase Inhibitors including acetazolamide,    dichlorphenamide, methazolamide, brinzolamide, dorzolamide, and the    like, or pharmaceutically acceptable salts or prodrugs thereof;-   Cholinergic Agonists including-   direct acting cholinergic agonists such as carbachol, pilocarpine    hydrochloride, pilocarbine nitrate, pilocarpine, and the like, or    pharmaceutically acceptable salts or prodrugs thereof;-   chlolinesterase inhibitors such as demecarium, echothiophate,    physostigmine, and the like, or pharmaceutically acceptable salts or    prodrugs thereof;-   Glutamate Antagonists and other neuroprotective agents such as Ca²⁺    channel blockers such as memantine, amantadine, rimantadine,    nitroglycerin, dextrophan, detromethorphan, CGS-19755,    dihydropyridines, verapamil, emopamil, benzothiazepines, bepridil,    diphenylbutylpiperidines, diphenylpiperazines, HOE 166 and related    drugs, fluspirilene, eliprodil, ifenprodil, CP-101,606, tibalosine,    2309BT, and 840S, flunarizine, nicardipine, nifedimpine, nimodipine,    barnidipine, verapamil, lidoflazine, prenylamine lactate, amiloride,    and the like, or pharmaceutically acceptable salts or prodrugs    thereof;-   Prostamides such as bimatoprost, or pharmaceutically acceptable    salts or prodrugs thereof; and-   Prostaglandins including travoprost, UFO-21, chloprostenol,    fluprostenol, 13,14-dihydro-chloprostenol, isopropyl unoprostone,    latanoprost and the like.-   Cannabinoids including CB1 agonists such as WIN-55212-2 and CP-55940    and the like, or pharmaceutically acceptable salts or prodrugs    thereof.

For treatment of diseases affecting the eye including glaucoma, thesecompounds can be administered topically, periocularly, intraocularly, orby any other effective means known in the art.

These compounds can also be used to treat or prevent conditionsaffecting the posterior part of the eye include maculopathies/retinaldegeneration such as non-exudative age related macular degeneration(ARMD), exudative age related macular degeneration (ARMD), choroidalneovascularization, diabetic retinopathy, acute macularneuroretinopathy, central serous chorioretinopathy, cystoid macularedema, and diabetic macular edema; uveitis/retinitis/choroiditis such asacute multifocal placoid pigment epitheliopathy, Behcet's disease,birdshot retinochoroidopathy, infectious (syphilis, lyme, tuberculosis,toxoplasmosis), intermediate uveitis (pars planitis), multifocalchoroiditis, multiple evanescent white dot syndrome (mewds), ocularsarcoidosis, posterior scleritis, serpiginous choroiditis, subretinalfibrosis and uveitis syndrome, Vogt-Koyanagi-and Harada syndrome;vasuclar diseases/exudative diseases such as retinal arterial occlusivedisease, central retinal vein occlusion, disseminated intravascularcoagulopathy, branch retinal vein occlusion, hypertensive funduschanges, ocular ischemic syndrome, retinal arterial microaneurysms,Coat's disease, parafoveal telangiectasis, hemi-retinal vein occlusion,papillophlebitis, central retinal artery occlusion, branch retinalartery occlusion, carotid artery disease (CAD), frosted branch angiitis,sickle cell retinopathy and other hemoglobinopathies, angioid streaks,familial exudative vitreoretinopathy, and Eales disease;traumatic/surgical conditions such as sympathetic ophthalmia, uveiticretinal disease, retinal detachment, trauma, conditions caused by laser,conditions caused by photodynamic therapy, photocoagulation,hypoperfusion during surgery, radiation retinopathy, and bone marrowtransplant retinopathy; proliferative disorders such as proliferativevitreal retinopathy and epiretinal membranes, and proliferative diabeticretinopathy; infectious disorders such as ocular histoplasmosis, oculartoxocariasis, presumed ocular histoplasmosis syndrome (POHS),endophthalmitis, toxoplasmosis, retinal diseases associated with HIVinfection, choroidal disease associate with HIV infection, uveiticdisease associate with HIV infection, viral retinitis, acute retinalnecrosis, progressive outer retinal necrosis, fungal retinal diseases,ocular syphilis, ocular tuberculosis, diffuse unilateral subacuteneuroretinitis, and myiasis; genetic disorders such as retinitispigmentosa, systemic disorders with accosiated retinal dystrophies,congenital stationary night blindness, cone dystrophies, Stargardt'sdisease and fundus flavimaculatus, Best's disease, pattern dystrophy ofthe retinal pigmented epithelium, X-linked retinoschisis, Sorsby'sfundus dystrophy, benign concentric maculopathy, Bietti's crystallinedystrophy, and pseudoxanthoma elasticum; retinal tears/holes such asretinal detachment, macular hole, and giant retinal tear; tumors such asretinal disease associated with tumors, congenital hypertrophy of theretinal pigmented epithelium, posterior uveal melanoma, choroidalhemangioma, choroidal osteoma, choroidal metastasis, combined hamartomaof the retina and retinal pigmented epithelium, retinoblastoma,vasoproliferative tumors of the ocular fundus, retinal astrocytoma, andintraocular lymphoid tumors; and miscellaneous other diseases affectingthe posterior part of the eye such as punctate inner choroidopathy,acute posterior multifocal placoid pigment epitheliopathy, myopicretinal degeneration, and acute retinal pigement epitheliitis.Preferably, the disease or condition is retinitis pigmentosa,proliferative vitreal retinopathy (PVR), age-related maculardegeneration (ARMD), diabetic retinopathy, diabetic macular edema,retinal detachment, retinal tear, uveitus, or cytomegalovirus retinitis.

These compounds are also useful in treating asthma.

EXAMPLES

Step a. 1-(2,4-Dimethoxybenzyl)-5-oxo-pyrrolidine-3-carboxylic AcidMethyl Ester

A solution of dimethyl itaconate (4.08 g, 25.8 mmol) in MeOH (3.2 mL)was added to a solution of 2,4-dimethoxybenzylamine (4.32 g, 25.8 mmol)in MeOH (9.6 mL) via cannula at room temperature. After 18 h at roomtemperature the reaction was concentrated in vacuo to afford crude1-(2,4-dimethoxybenzyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl esteras a viscous oil.

Step b. 1-(2,4-Dimethoxybenzyl)-4-hydroxymethyl-pyrrolidin-2-one

Sodium borohydride (9.76 g, 25.8 mmol) was added in three portions to asolution of the crude ester from step 1 (˜25.8 mmol) in ethanol (111 mL)at 0° C. The reaction was allowed to warm to room temperature. After 18h at room temperature, the reaction was quenched with saturated aqueousNH₄Cl (100 mL) and the ethanol was removed in vacuo. The remainingaqueous mixture was extracted with EtOAc (3×100 mL). Combined extractswere dried (Na₂SO₄), filtered and concentrated in vacuo to afford crude1-(2,4-dimethoxybenzyl)-4-hydroxymethyl-pyrrolidin-2-one.

Step c.4-(tert-Butyldimethylsilanyloxymethyl)-1-(2,4-dimethoxybenzyl)-pyrrolidin-2-one

Imidazole (4.39 g, 64.5 mmol) and tert-butyldimethylsilyl chloride (4.28g, 28.4 mmol) were added to a solution of the crude alcohol from step 2(˜25.8 mmol) in DMF (36 mL). After 18 h at room temperature, thereaction was diluted with hexane (400 mL) and washed with water (2×200mL) and brine (200 mL). The organic phase was dried (MgSO₄), filteredand concentrated to afford 9.47 g (97%) of4-(tert-butyldimethylsilanyloxymethyl)-1-(2,4-dimethoxybenzyl)-pyrrolidin-2-oneas a colorless oil.

Step d.7-[(3R*,4R*)-4-(tert-Butyldimethylsilanyloxymethyl)-1-(2,4-dimethoxybenzyl)-2-oxo-pyrrolidin-3-yl]-hept-5-ynoicAcid Methyl Ester

Lithium diisopropylamide (1.5 M in cyclohexane, 9.22 mL, 13.83 mmol) wasadded to a solution of4-(tert-butyldimethylsilanyloxymethyl)-1-(2,4-dimethoxybenzyl)-pyrrolidin-2-one(2.63 g, 6.93 mmol) in THF (41 mL) at −78° C. under nitrogen. After 30min at −78° C., hexamethylphosphoramide (3.61 mL, 20.7 mmol) was addeddropwise. After 30 min at −78° C., methyl 7-iodohept-5-ynoate (5.52 g,20.7 mmol) in THF (20 mL +3 mL) was added. The reaction mixture wasallowed to warm to room temperature. After 18 h at room temperature, thereaction was quenched with saturated aqueous NH₄Cl and extracted withEtOAc (3×50 mL). Combined extracts were dried (Na₂SO₄), filtered andconcentrated in vacuo. The crude residue was purified by flash columnchromatography on silica gel (40% EtOAc/hexane) to afford 579 mg (16%)of7-[(3R*,4R*)-4-(tert-butyldimethylsilanyloxymethyl)-1-(2,4-dimethoxybenzyl)-2-oxo-pyrrolidin-3-yl]-hept-5-ynoicacid methyl ester.

Step e.7-[(3R*,4R*)-1-(2,4-Dimethoxybenzyl)-4-hydroxymethyl-2-oxo-pyrrolidin-3-yl]-hept-5-ynoicAcid Methyl Ester

Tetrabutylammonium fluoride (1.0 M in THF, 4.0 mL, 4.0 mmol) was addedto a solution of7-[(3R*,4R*)-4-(tert-butyldimethylsilanyloxymethyl)-1-(2,4-dimethoxybenzyl)-2-oxo-pyrrolidin-3-yl]-hept-5-ynoicacid methyl ester (680 mg, 1.31 mmol) in THF (13 mL) at 0° C. undernitrogen. The reaction was allowed to warm to room temperature. After 18h at room temperature, THF was removed in vacuo and the residue wastaken up in EtOAc (50 mL). The organic phase was washed with water (2×20mL) and brine (20 mL) then dried (Na₂SO₄), filtered and concentrated invacuo. The crude residue was purified by flash column chromatography onsilica gel (85% EtOAc/hexane→EtOAc, gradient) to afford 304 mg (57%) of7-[(3R*,4R*)-1-(2,4-dimethoxybenzyl)-4-hydroxymethyl-2-oxo-pyrrolidin-3-yl]-hept-5-ynoicAcid Methyl Ester.

Step f.

This step is carried out with a procedure analogous to that disclosed inUnited States Provisional Application Ser. No. 60/644,069, filed Jan.14, 2005 (now PCT/US 2006/000831 filed Jan. 10, 2006) (FIG. 1, Example1, step 1).

Step g.

(DDQ, 90 mg, 0.40 mmol) is added to the compound (˜0.27 mmol) in CHCl₃(˜1.3 mL) and water (70 μL) at room temperature. After 42 h at roomtemperature, the mixture is filtered through celite, washing with CHCl₃,concentrated in vacuo, and purified by flash column chromatography onsilica gel (75% EtOAc/hexane→EtOAc→5% MeOH/EtOAc, gradient).

Step h.

Sodium borohydride (5.4 mg, 0.14 mmol) is added to a suspension ofnickel (II) chloride (37 mg, 0.29 mmol) and 95% ethanol (2.3 mL). Themixture immediately turns black. More sodium borohydride (˜1 mg) isadded to generate a fine black suspension. After 15 min at roomtemperature, ethylene diamine (31 μL, 0.46 mmol) is added. After another15 min at room temperature, the alkyne (˜0.057 mmol) in 95% ethanol (0.3mL) is added via cannula. A hydrogen atmosphere is established byevacuating and refilling with hydrogen (3x) and the reaction mixture isstirred under a balloon of hydrogen for 18 h. The reaction mixture isfiltered through celite, washing with ethanol, and the filtrate isconcentrated in vacuo. Purification of the resulting residue by flashcolumn chromatography (8% MeOH/CH₂Cl₂) affords the desired alkene.

Step j.

Palladium on carbon (5 wt %, 10 mg) is added to a solution of the alkyne(˜0.028 mmol) in EtOAc (˜0.6 mL). A hydrogen atmosphere is establishedby evacuating and refilling with hydrogen (3x) and the reaction mixtureis stirred under a balloon of hydrogen for 18 h. The reaction mixture isfiltered through celite, washing with EtOAc, and the filtrate isconcentrated in vacuo. Purification of the resulting residue by flashcolumn chromatography (CH₂Cl₂→8% MeOH/CH₂Cl₂) affords the desiredalkane.

Step i.

Ester hydrolysis. Rabbit liver esterase (134 units/mg, 1 mg) is added tothe methyl ester (˜0.012 mmol) in acetonitrile (˜0.1 mL) and pH 7.2phosphate buffer (˜0.58 mL). After 18 h, methanol (5 mL) is added andthe reaction mixture is concentrated to dryness in vacuo. Purificationof the residue by flash column chromatography on silica gel (CH₂Cl₂→10%MeOH/CH₂Cl₂, gradient) affords the desired carboxylic acid.

Step j.

a. Triethylamine and ethyl chloroformate are added sequentially to asolution of the compound formed in step h or j in CH₂Cl₂ at roomtemperature. After 2.5 h, triethylamine and ethylene glycol are added.After stirring overnight at room temperature, the reaction mixture ispartitioned between H₂O and CH₂Cl₂. The phases are separated and theaqueous phase is extracted with CH₂Cl₂ (2x). The combined organic phaseis washed with 1 N HCl then dried (MgSO₄), filtered and concentrated invacuo. Purification of the residue by flash column chromatography onsilica gel (10% CH₃OH/CH₂Cl₂) affords the desired compound.

b. Triethylamine and ethyl chloroformate are added sequentially to asolution of the compound formed in step h or j in CH₂Cl₂ at roomtemperature. After 2.5 h, triethylamine and 4-(2-hydroxyethyl)-morphineare added. After stirring overnight at room temperature, the reactionmixture is partitioned between H₂O and CH₂Cl₂. The phases are separatedand the aqueous phase is extracted with CH₂Cl₂ (2x). The combinedorganic phase is washed with 1 N HCl then dried (MgSO₄), filtered andconcentrated in vacuo. Purification of the residue by flash columnchromatography on silica gel (10% CH₃OH/CH₂Cl₂) affords the desiredcompound the desired compound.

The enantiomers may be resolved at several stages. For instance, theintermediate alcohol (after step e or a similar alcohol lacking thealpha chain) may be resolved by enzymatic acylation or deacylation of acorresponding ester derivative. Several precedents exist in the art.

Other methods well known in the art may be used to accomplish thesynthesis outlined above.

Different alpha chains may be added by a variety of methods known in theart. For example, the 7-iodohept-5-ynoate of step d may be substitutedwith compound 12-3 (FIG. 13) of U.S. patent application Ser. No.11/009,298, filed on Dec. 10, 2004, now U.S. Pat. No. 7,091,231, issuedAug. 15, 2006. The 7-iodohept-5-ynoate of step d may also be substitutedwith a compound such as that described by Kotake (J. Med. Chem. 1994,37, 1616-1624). Other methods are also envisioned, such as addition ofmethyl 5-(3-bromopropyl)thiophene-2-carboxylate (synthesis described inWO94/13295).

Treatment of inflammatory bowel disease may be accomplished by theadministration of the compounds described herein to the sufferingmammal. Inflammatory bowel disease describes a variety of diseasescharacterized by inflammation of the bowels including, but not limitedto, ulcerative colitis and Crohn's disease. Treatment may beaccomplished by oral administration, by suppository, or parenteraladministration, or some other suitable method.

While not intending to limit the scope of the invention in any way,delivery of the compounds disclosed herein to the colon via oral dosageforms may be accomplished by any of a number of methods known in theart. For example, reviews by Chourasia and Jain in J Pharm PharmaceutSci 6 (1): 33-66, 2003 and Shareef et. al (AAPS PharmSci 2003; 5 (2)Article 17) describe a number of useful methods. While not intending tolimit the scope of the invention in any way these methods include 1)administration of a prodrug, including an azo or a carbohydrate basedprodrug; 2) coating the drug with, or encapsulating or impregnating thedrug into a polymer designed for delivery to the colon, 3) time releaseddelivery of the drug, 4) use of a bioadhesive system; and the like.

While not intending to be bound in any way by theory, it is believedthat intestinal microflora are capable of reductive cleavage of an azobond leaving the two nitrogen atoms as amine functional groups. Whilenot intending to limit the scope of the invention in any way, the azoprodrug approach has been used to deliver to 5-aminosalicylic acid tothe colons of humans in clinical trials for the treatment ofinflammatory bowel disease. It is also believed that bacteria of thelower GI also have enzymes which can digest glycosides, glucuronides,cyclodextrins, dextrans, and other carbohydrates, and ester prodrugsformed from these carbohydrates have been shown to deliver the parentactive drugs selectively to the colon. For example, in vivo and in vitrostudies on rats and guinea pigs with prodrugs of dexamethasone,prednisolone, hydrocortisone, and fludrocortisone, suggest thatglycoside conjugates may be useful for the delivery of steroids to thehuman colon. Other in vivo studies have suggested that glucouronide,cyclodextrin, and dextran prodrugs of steroids or non-steroidalanti-inflammatory drugs are useful for delivery of these drugs to thelower GI tract. An amide of salicylic acid and glutamic acid has beenshown to be useful for the delivery of salicylic acid to the colon ofrabbit and dog.

While not intending to limit the scope of the invention in any way,carbohydrate polymers such as amylase, arabinogalactan, chitosan,chondroiton sulfate, dextran, guar gum, pectin, xylin, and the like, orazo-group containing polymers can be used to coat a drug compound, or adrug may be impregnated or encapsulated in the polymer. It is believedthat after oral administration, the polymers remain stable in the upperGI tract, but are digested by the microflora of the lower GI thusreleasing the drug for treatment.

Polymers which are sensitive to pH may also be used since the colon hasa higher pH than the upper GI tract. Such polymers are commerciallyavailable. For example, Rohm Pharmaceuticals, Darmstadt, Germany,commercially provides pH dependent methacrylate based polymers andcopolymers which have varying solubilities over different pH rangesbased upon the number of free carboxylate groups in the polymer underthe tradename Eudragit®. Several Eudragit® dosage forms are currentlyused to deliver salsalazine for the treatment of ulcerative colitis andCrohn's disease. Time release systems, bioadhesive systems, and otherdelivery systems have also been studied.

Compounds 1a, 1b, 2a and 2b from above are tested in vivo to measure itsability to reduce intraocular pressure. Compound 1a is tested innormotensive dogs. The intraocular pressure (IOP) decreases frombaseline. This compound is also tested in laser-induced hypertensivemonkeys, the IOP decreases from baseline.

Compound 1b is tested in normotensive dogs. The intraocular pressure(IOP) decreases from baseline. This compound is also tested inlaser-induced hypertensive monkeys, the IOP decreases from baseline.

Compound 2a is tested in normotensive dogs. The intraocular pressure(IOP) decreases from baseline. This compound is also tested inlaser-induced hypertensive monkeys, the IOP decreases from baseline.

Compound 2b is tested in normotensive dogs. The intraocular pressure(IOP) decreases from baseline. This compound is also tested inlaser-induced hypertensive monkeys, the IOP decreases from baseline.

The foregoing description details specific methods and compositions thatcan be employed to practice the present invention, and represents thebest mode contemplated. However, it is apparent for one of ordinaryskill in the art that further compounds with the desired pharmacologicalproperties can be prepared in an analogous manner, and that thedisclosed compounds can also be obtained from different startingcompounds via different chemical reactions. Similarly, differentpharmaceutical compositions may be prepared and used with substantiallythe same result. Thus, however detailed the foregoing may appear intext, it should not be construed as limiting the overall scope hereof;rather, the ambit of the present invention is to be governed only by thelawful construction of the appended claims.

1. A compound of the formula

or a pharmaceutically acceptable salt thereof; Y is

A is —(CH₂)₆—, cis —CH₂CH═CH—(CH₂)₃—, or —CH₂C≡C—(CH₂)₃—, wherein 1 or 2carbon atoms may be substituted with S or O; or A is—(CH₂)_(m)—Ar—(CH₂)_(o)— wherein Ar is interarylene orheterointerarylene, the sum of m and o is from 1 to 4, and wherein oneCH₂ may be substituted with S or O; X is S or O; R is H; or alkyl, acyl,alkylsulfonyl, or alkylsulfamoyl having from 1 to 6 carbon atoms; and Dis aryl or heteroaryl.
 2. The compound of claim 1 wherein A is5-(3-propyl)thiophen-2-yl.
 3. The compound of claim 1 wherein A is6-hexyl.
 4. The compound of claim 1 wherein A is (Z)-6-hex-4-enyl. 5.The compound of claim 1 wherein B is substituted phenyl.
 6. The compoundof claim 1 of the formula

or a pharmaceutically acceptable salt thereof.
 7. The compound of claim1 of the formula

or a pharmaceutically acceptable salt thereof.
 8. The compound of claim1 of the formula

or a pharmaceutically acceptable salt thereof wherein R⁴ isindependently a substituent having from 0 to 10 carbon atoms and from 0to 5 heteroatoms selected from the group consisting of Cl, F, Br, O, N,and S; q is 0, 1, 2, 3, or 4; and wherein two R⁴ moieties may form aring with two carbon atoms of the phenyl ring.
 9. The compound of claim1 of the formula

or a pharmaceutically acceptable salt thereof.
 10. The compound of claim1 of the formula

or a pharmaceutically acceptable salt thereof; wherein R⁴ isindependently a substituent having from 0 to 10 carbon atoms and from 0to 5 heteroatoms selected from the group consisting of Cl, F, Br, O, N,and S; q is 0, 1, 2, 3, or 4; and wherein two R⁴ moieties may form aring with two carbon atoms of the phenyl ring.
 11. A compound of claim 1of the formula

or a pharmaceutically acceptable salt thereof; wherein R⁴ isindependently a substituent having from 0 to 10 carbon atoms and from 0to 5 heteroatoms selected from the group consisting of Cl, F, Br, O, N,and S; q is 0, 1, 2, 3, or 4; and wherein two R⁴ moieties may form aring with two carbon atoms of the phenyl ring.
 12. A compound of claim 1of the formula

or a pharmaceutically acceptable salt thereof.
 13. A method comprisingadministering a compound according to claim 1 for the treatment ofbaldness.